Objective To study the protective effect of valeric acid combined with sodium valproate (VPA) on pentylenetetrazole-induced epilepsy mice and P-glycoprotein ( P-GP) expression. Methods Mice were divided into six groups: normal control group, model control group, VPA group, and valeric acid +VPA group ( low, medium, and high doses). The expression of P-GP and caspase-3 active fragments in brain tissue and the rate of neuronal apoptosis in the cerebral cortex were analyzed. Results Compared with the VPA group, the seizure duration in all dose valeric acid + VPA groups was shortened, and the seizure latency in the middle-dose valeric acid group was prolonged. The seizure level in the middle-dose and high-dose valeric acid groups was lower than that in the VPA group. P-GP in the cerebral cortex of the model control group was significantly higher than that of the normal control group. The expression of P-GP protein in the VPA group was not significantly different compared with the model control group. Levels of P-GP protein were decreased in all dose valeric acid + VPA groups compared with the VPA group. The expression of caspase-3 was decreased compared with the VPA group. The apoptosis rate in each dose valeric acid + VPA group was lower than that in the VPA group. Conclusions Valeric acid may reduce the severity of seizures in pentylenetetrazol ignition / VPA-treated mice through a mechanism related to reduced P-GP expression.